Design and development of lipid nanoparticle formulations for brain gene therapy.
Overview
- University of British Columbia, Department of Medical Genetics, C201-4500 Oak Street, Vancouver, BC V6H 3N1, Canada
- NanoVation Therapeutics, 2665 East Mall, 2nd Floor, Vancouver, BC V6T 1Z4, Canada
- University of British Columbia, Department of Biochemistry and Molecular Biology, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
- University of British Columbia, Department of Chemistry, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
- Incisive Genetics, Inc., 200 – 980 George Street, Vancouver, BC V6A 0H9, Canada
- Polymorphic BioSciences, Inc., 2665 East Mall, 2nd Floor, Vancouver, BC V6T 1Z4, Canada
Abstract
Many genetic neurological diseases are caused by toxic gain-of-function of a mutant protein or loss-of-function of a wild-type protein. Treatment of these disorders may be feasible using gene therapy, which requires delivering therapeutic agents to affected brain regions and cells. Lipid nanoparticles (LNPs) have significant potential for this purpose: the clinical safety and efficacy of LNP systems is well-established, and neurons are amenable to LNP-mediated transfection. To adapt LNP technology for brain gene therapy applications, we iteratively designed LNPs to deliver nucleic acids to ex vivo primary neurons, and evaluated optimized formulations in vivo in the brain. Our approach improved ex vivo LNP potency over 1.7-fold for siRNA-containing systems and over 22-fold for mRNA-containing systems, and identified distinct compositions optimal for siRNA and mRNA delivery. We show that the activity of ex vivo-optimized LNPs is not always correlated with in vivo activity in murine striatum and establish the apparent pKa of ionizable cationic lipids as an important contributor to LNP efficacy in both model systems. Collectively, we demonstrate robust delivery of multiple macromolecular payloads to primary neurons ex vivo and to the brain in vivo and validate the utility of LNP systems for gene knockdown and protein replacement brain gene therapies.
Reproduced under the paper's license (CC BY), from the paper cited above.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Versions
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Version 2, 28 September 2026
- Authors: added Sarah B. Thomson (0000-0001-9407-1245); Blair R. Leavitt (0000-0002-4532-766X); removed Sarah B. Thomson; Blair R. Leavitt
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 6 keywords, 2 funders, 64 references.
Cite
This paper
Thomson, S. B., de Moura Gomes, A., Kazemian, P., Kurek, D. Z., Kulkarni, J. A., Sadaati, F., Wagner, P. K., Petkau, T. L., Ciufolini, M. A., Cullis, P. R., & Leavitt, B. R. (2026). Design and development of lipid nanoparticle formulations for brain gene therapy. Molecular therapy. Nucleic acids, 37(3), 103025. https://
BibTeX
@article{thomson2026desi
author = {Thomson, Sarah B. and de Moura Gomes, Alissandra and Kazemian, Pardis and Kurek, Daniel Z. and Kulkarni, Jayesh A. and Sadaati, Fariba and Wagner, Pamela K. and Petkau, Terri L. and Ciufolini, Marco A. and Cullis, Pieter R. and Leavitt, Blair R.},
title = {{Design and development of lipid nanoparticle formulations for brain gene therapy}},
journal = {Molecular therapy. Nucleic acids},
year = {2026},
month = jul,
volume = {37},
number = {3},
pages = {103025},
publisher = {American Society of Gene \& Cell Therapy},
issn = {2162-2531},
doi = {10.1016/
url = {https://
pmid = {42597608},
pmcid = {PMC13469846}
}
RIS
TY - JOUR
AU - Thomson, Sarah B.
AU - de Moura Gomes, Alissandra
AU - Kazemian, Pardis
AU - Kurek, Daniel Z.
AU - Kulkarni, Jayesh A.
AU - Sadaati, Fariba
AU - Wagner, Pamela K.
AU - Petkau, Terri L.
AU - Ciufolini, Marco A.
AU - Cullis, Pieter R.
AU - Leavitt, Blair R.
TI - Design and development of lipid nanoparticle formulations for brain gene therapy
T2 - Molecular therapy. Nucleic acids
J2 - Mol Ther Nucleic Acids
PY - 2026
DA - 2026/
VL - 37
IS - 3
SP - 103025
SN - 2162-2531
PB - American Society of Gene & Cell Therapy
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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